Uniformity calibration for large area XY strip parallel plate ionization chamber.

Demand for large area parallel plate ionization chamber (PPIC) or large area ionization chamber (LAIC) has risen in recent years due to several advantages of the large effective area in monitoring therapeutic radiation beams. PPICs are designed for the measurements of beam profile and dosimetry in radiation therapy quality assurance (QA) procedures.Objective. Heterogeneous responses over the large sensitive area pose an undeniable concern for the straightforward applications of PPICs in clinical dosimetry. Uniformity calibration for the detector response is thus essential for the accurate performance of each PPIC unit.Approach.A large area XY strip PPIC, characterized by a large effective area of 345.44 × 345.44 mm2and 256 readout channels, was investigated in this study. A new systematic uniformity calibration is developed to improve the lateral response of the PPIC over the measurements for both narrow beams and large square field beams. A 2D response map of the PPIC was obtained by a spot-scanning method using a compact x-ray tube (mini x-ray). The mini x-ray, providing stable radiation (uncertainty <0.1%), was moved with a step size of 20 mm in 2 dimensions across the entire PPIC surface to collect a complete spot scan. Different uniformity calibration methods were introduced for the measurement of the PPIC by adopting the information from the detector 2D response map.Main results.Deviation of the detector response, before calibration, was observed to reach about 7% for the testing PPIC unit which is much higher than the recommended uniformity response of 1% (IAEA TRS-398). The uniformity response of the PPIC improved significantly to less than 1% across the detector surface after calibration.Significance.The proposed methods enable the practical application of PPIC in routine clinical dosimetry and can be reliably adopted by any radiation facility to perform daily and monthly QA.

Combination immunosuppressant therapy and lupus nephritis outcome: a hospital-based study.

Lupus nephritis (LN) is the leading cause of mortality in lupus patients. This study aimed to investigate the treatment outcome and renal histological risk factors of LN in a tertiary referral center. Between 2006 and 2017, a retrospective observational study enrolled 148 biopsy-proven LN patients. After propensity score matching, 75 cases were included for further analysis. The classification and scoring of LN were assessed according to the International Society of Nephrology/Renal Pathology Society. Treatment response was evaluated by daily urine protein and urinalysis at two years after commencing induction treatment and the development of end-stage renal disease (ESRD). In total, 50.7% patients achieved complete remission (CR) or partial remission (PR), while 49.3% patients were categorized as nonresponders. Therapeutic responses in terms of CR/PR rates were associated with Systemic Lupus Erythematosus Disease Activity Index scores (odds ratio (OR): 1.34, 95% confidence interval (CI): 1.12-1.60, p = 0.001). Moreover, higher baseline creatinine levels (hazard ratio (HR): 2.10, 95% CI: 1.29-3.40, p = 0.003), higher renal activity index (HR: 1.30, 95% CI: 1.07-1.58, p = 0.008) and chronicity index (HR: 1.40, 95% CI: 1.06-1.85, p = 0.017) predicted ESRD. Among pathological scores, cellular crescents (HR: 4.42, 95% CI: 1.01-19.38, p = 0.049) and fibrous crescents (HR: 5.93, 95% CI: 1.41-24.92, p = 0.015) were independent risk factors for ESRD. In conclusion, higher lupus activity was a good prognostic marker for renal remission. Renal histology was predictive of ESRD. Large-scale prospective studies are required to verify the efficacy of mycophenolate in combination with azathioprine or cyclosporine in LN patients.

The role of reactive oxygen species scavenging enzymes in the development of septic loosening after total hip replacement.

In this study of 41 patients, we used proteomic, Western blot and immunohistochemical analyses to show that several reactive oxygen species scavenging enzymes are expressed differentially in patients with primary osteoarthritis and those with non-loosening and aseptic loosening after total hip replacement (THR). The patients were grouped as A (n = 16, primary THR), B (n = 10, fixed THR but requiring revision for polyethylene wear) and C (n = 15, requiring revision due to aseptic loosening) to verify the involvement of the identified targets in aseptic loosening. When compared with Groups A and B, Group C patients exhibited significant up-regulation of transthyretin and superoxide dismutase 3, but down-regulation of glutathione peroxidase 2 in their hip synovial fluids. Also, higher levels of superoxide dismutase 2 and peroxiredoxin 2, but not superoxide dismutase 1, catalase and glutathione perioxidase 1, were consistently detected in the hip capsules of Group C patients. We propose that dysregulated reactive oxygen species-related enzymes may play an important role in the pathogenesis and progression of aseptic loosening after THR.

Antinucleosome antibodies as a potential biomarker for the evaluation of renal pathological activity in patients with proliferative lupus nephritis.

The objective of this study is to evaluate the correlation between antinucleosome antibodies and renal pathological activity in patients with proliferative lupus nephritis (LN). We evaluated 36 patients with proliferative LN, 14 non-renal lupus patients and 10 healthy volunteers. Lupus activity was assessed using the British Isles Lupus Assessment Group 2004 (BILAG 2004) index, serum anti-double stranded DNA (anti-dsDNA) levels, serum complement levels and daily urinary protein levels. All 36 lupus nephritis patients received renal biopsy. Antinucleosome antibodies were detected by enzyme-linked immunosorbent assay (ELISA). Our results showed that levels of serum antinucleosome antibodies were significantly higher in LN patients (median 90.35 units/ml, interquartile range [IQR] 37.38-135.23) than in non-renal SLE patients (median 5.45 units/ml, IQR 2.6-28.93, p <0.05) and in healthy volunteers (median 3.35 units/ml, IQR 2.95-5.23, p <0.001). Serum levels of antinucleosome antibodies were positively correlated with BILAG index (Spearman's r = 0.645, p <0.001) and serum anti-dsDNA antibody levels (r(s) = 0.644, p <0.01), while serum levels of antinucleosome antibodies were negatively correlated with serum levels of C3 (r(s) = -0.400, p <0.01) and C4 (r(s) = -0.300, p <0.05). Serum levels of antinucleosome antibodies were positively correlated with the histological activity index of LN (r(s) = 0.368, p <0.05). However, there was no significant correlation between serum levels of antinucleosome antibodies and the histological chronicity index. In conclusion, the serum level of antinucleosome antibodies is a potential biomarker for early recognition of renal involvement and evaluation of disease activity in SLE. Our preliminary results suggested that serum levels of antinucleosome antibodies might be a potential biomarker in evaluating pathological activity of LN.

Interferon-inducible protein-10 as a marker to detect latent and active tuberculosis in rheumatoid arthritis.

SETTING: effective tuberculosis (TB) screening should be performed before anti-tumour necrosis factor alpha (TNF-α) treatment in rheumatoid arthritis (RA). The usefulness of the tuberculin skin test (TST) and QuantiFERON®-TB Gold (QFT-G) for detecting latent tuberculosis infection (LTBI) is limited. OBJECTIVE: we tested the diagnostic performance of interferon-gamma (IFN-γ) inducible protein 10 (IP-10) and IFN-γ for detecting LTBI in RA patients receiving anti-TNF-α treatment. DESIGN: IP-10 levels were determined by enzyme-linked immunosorbent assay in 56 RA patients and 18 active TB patients. TST was performed using the Mantoux method and QFT-G was performed by measuring IFN-γ levels in whole blood treated with TB-specific antigens. RESULTS: twenty-four (42.9%) TST-positive patients were defined as having LTBI. Significantly higher levels of baseline, early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) stimulated IP-10 were observed in active TB patients (median 209.9 pg/ml, 899.0 pg/ml and 880.2 pg/ml, respectively) and RA patients with LTBI (165.3 pg/ml, 904.4 pg/ml and 747.5 pg/ml, respectively), compared to those without LTBI (89.3 pg/ml, 579.4 pg/ml and 515.0 pg/ml, respectively). Baseline IP-10 has high sensitivity (83.3% and 100%) and medium specificity (67.9% and 59.6%), while ESAT-6-stimulated IP-10 has high sensitivity (87.5% and 100%) and specificity (85.7% and 71.2%) for detecting LTBI and TB. The performance of IP-10 is superior to IFN-γ for detecting LTBI (TST+) and active TB. CONCLUSION: IP-10 may be used for detecting LTBI and as a potential biomarker to identify active TB in RA patients receiving anti-TNF-α treatment.

Association of Epstein-Barr virus infection with systemic lupus erythematosus in Taiwan.

An association between Epstein-Barr virus (EBV) infection and systemic lupus erythematosus (SLE) has been suggested from previous serologic evidence. Since most adults in Taiwan are EBV-infected, seroepidemiologic studies based on standard assays for EBV are unlikely to dissociate SLE patients and control groups. We reexamine this question by using novel methodologies in which IgA anti-EBV-coded nuclear antigens-1 (EBNA-1) and IgG anti-EBV DNase antibodies were analysed by ELISA, and EBV viral loads were detected by real-time quantitative PCR for 93 adult SLE patients and 370 age-, sex- and living place-matched healthy controls in Taiwan. The specificities of antibodies for extractible nuclear antigens were determined by Western blot. Our results show that IgA anti-EBV EBNA1 antibodies were detectable in 31.2% SLE patients but only in 4.1% of controls (odds ratio [OR] = 10.72, 95% confidence interval [CI] = 5.19-22.35; P < 10(-7)), IgG anti-EBV DNase antibodies were detected in 53.8% SLE patients but only in 12.2% controls (OR = 8.40, 95% CI = 4.87-14.51; P < 10(-7)). EBV DNA was amplifiable from the sera of 41.9% SLE patients but from only 3.24% controls (P < 0.05). A significant association of IgG anti-EBV DNase antibodies with anti-Sm/RNP antibodies was observed (P < 0.005). The higher seroreactivity and higher copy numbers of EBV genome indicated association of EBV infection with SLE in Taiwan.

Upregulation of endothelial heme oxygenase-1 expression through the activation of the JNK pathway by sublethal concentrations of acrolein.

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde that is present in cigarette smoke. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated by various such electrophilic compounds. In this study, the regulatory effects of acrolein upon the expression of HO-1 were investigated in endothelial cells (ECs). We demonstrate that acrolein induces the elevation of HO-1 protein levels, and subsequent enzyme activity, at non-cytotoxic concentrations. An additional alpha,beta-unsaturated aldehyde, cinnamaldehyde, was also found to increase HO-1 expression and have less cytotoxicity than acrolein. Moreover, acrolein-mediated HO-1 induction is abrogated in the presence of actinomycin D and cycloheximide. Nrf2 is a transcription factor involved in the induction of HO-1 through an antioxidant response element (ARE) in the promoter region of the HO-1 gene. We show that acrolein induces Nrf2 translocation and ARE-luciferase reporter activity. Acrolein was also found to induce the production of both superoxide and H2O2 at levels greater than 100 microM. However, with the exception of NAC, no antioxidant generated any effect upon acrolein-dependent HO-1 expression in ECs. Our present findings suggest that reactive oxygen species (ROS) may not be a major modulator for HO-1 induction. Using buthionine sulfoximine to deplete the intracellular GSH levels further enhanced the effects of acrolein. We also found that cellular GSH level was rapidly reduced after both 10 and 100 microM acrolein treatment. However, after 6 h of exposure to ECs, only 10 microM acrolein treatment increases GSH level. In addition, only the JNK inhibitor SP600125 and tyrosine kinase inhibitor genistein had any significant inhibitory impact upon the upregulation of HO-1 by acrolein. Pretreatment with a range of other PI3 kinase inhibitors, including wortmannin and LY294002, showed no effects. Hence, we show in our current experiments that a sublethal concentration of acrolein is in fact a novel HO-1 inducer, and we further identify the principal underlying mechanisms involved in this process.

15-Deoxy-Delta(12,14)-prostaglandin J(2) suppresses IL-6-induced STAT3 phosphorylation via electrophilic reactivity in endothelial cells.

In this study, the effects of 15d-PGJ(2) were investigated in IL-6-activated endothelial cells (ECs). 15d-PGJ(2) was found to abrogate phosphorylation on tyr705 of STAT3 in IL-6-treated ECs, in a dose- and time-dependent manner, but did not inhibit serine phosphorylation of STAT3 and the upperstream JAK2 phosphorylation. Other PPAR activators, such as WY1643 or ciglitazone, had no effect upon IL-6-induced STAT3 phosphorylation. Additionally, neither orthovanadate nor l-NAME treatment reverses the inhibition of STAT3 phosphorylation by 15d-PGJ(2). Otherwise, the effect of 15d-PGJ(2) requires the alpha,beta-unsaturated carbonyl group in the cyclopentane ring. A 15d-PGJ(2) analog, 9,10-Dihydro-15d-PGJ(2), which lack alpha,beta-unsaturated carbonyl group showed no increase in ROS production and no effect in inhibition of IL-6-induced STAT3 phosphorylation. The electrophilic compound, acrolein, mimics the inhibition effect of 15d-PGJ(2). Among the antioxidants, only NAC and glutathione reversed the effects of 15d-PGJ(2). NAC, glutathione and DTT all reversed the inhibition of STAT3 phosphorylation when preincubated with 15d-PGJ(2). The inhibition of ICAM-1 gene expression by 15d-PGJ(2) was abrogated by NAC and glutathione in IL-6-treated ECs. Taken together, these results suggest that 15d-PGJ(2) inhibits IL-6-stimulated phosphorylation on tyr705 of STAT3 dependent on its own electrophilic reactivity in ECs.

Resveratrol suppresses IL-6-induced ICAM-1 gene expression in endothelial cells: effects on the inhibition of STAT3 phosphorylation.

Resveratrol, a polyphenolic phytoaxelin present in red wine, has been suggested to protect against atherosclerosis and cardiovascular disease because of its antioxidant effects. Intercellular adhesion molecule (ICAM-1), induced by cytokines, has been hypothesized to play a role in the early events during atherosclerosis. In this study we tested the effects of resveratrol upon both IL-6-induced ICAM-1 gene expression and its underlying signaling pathways in endothelial cells (ECs). Resveratrol was found to inhibit both TNFalpha- and IL-6-induced ICAM-1 gene expression at the promoter, transcriptional and protein levels. Resveratrol also abrogates the tyr705 phosphorylation of STAT3 in IL-6-treated ECs, in a dose- and time-dependent manner. Although quercetin had similar effects, resveratrol showed higher inhibitory properties following 2-4 h pretreatments. Resveratrol has been shown to induce the activity of endothelial nitric oxide synthase (eNOS) and increase NO production. Consistent with this, the treatment of ECs with a NO donor (SNAP) reduces IL-6-induced STAT3 phosphorylation. Conversely, exposure of ECs to a NOS inhibitor reversed the effects of resveratrol upon IL-6-induced STAT3 phosphorylation. Furthermore, ECs transfected with constitutively active Rac1 (RacV12) showed increases in ICAM-1 promoter activity, intracellular reactive oxygen species (ROS) levels and STAT3 phosphorylation, and these increases were attenuated by resveratrol treatment. In summary, we demonstrate for the first time that resveratrol inhibits IL-6-induced ICAM-1 gene expression, in part, by interfering with Rac-mediated pathways via the attenuation of STAT3 phosphorylation. This study therefore provides important new insights that may contribute to the proposed beneficial effects of resveratrol in endothelial responses to cytokines during inflammation.